Macrophage-targeted polysaccharide nano-immunomodulators with spatial- and time-programmed drug release for cancer therapy

Reprogramming tumor-associated macrophages (TAMs) represents a promising strategy to reverse tumor immunosuppressive microenvironment (TIME) for cancer immunotherapy. However, the deficiency of macrophage cells in solid tumors requires targeted drug delivery to accomplish efficient immune activation while reducing the adverse side-effects. Meanwhile, the negative feedback of TAM activation compromises immunotherapy efficacy by inducing T cell exhaustion. In this work, we report a type of macrophage-targeted polysaccharide nano-immunomodulators (Dex-RN) with spatial- and time-programmed drug release for cancer therapy by activating the TLR7/8 pathways and inhibiting the negative IDO pathway. Dex-RN exhibited high TAM targeting capability in vivo with 40.8 % for D10-RN and 44.3 % for D70-RN as compared with the control (19.0 %), and possessed fast TLR7/8 agonist but slow IDO inhibitor release kinetics to address the impact of the negative feedback of TLR7/8 pathway activation. Consequently, Dex-RN generated significantly enhanced macrophage M1 polarization efficiency with superior expression levels of cell surface markers and cytokines. In a 4T1 murine tumor model, Dex-RN showed enhanced tumor growth inhibition (66 %) compared with free drug mixture (43 %), and potentiated cancer immunotherapy by inducing macrophage M1 polarization, activating CD8⁺ T cells and inhibiting Treg cells. Thus, this work highlights the conception of a spatial- and time-programmed polysaccharide nano-immunomodulator for TAM-mediated cancer immunotherapy.